Study: 7-hydroxymitragynine Metabolizes into the More Potent ‘Mitragynine Pseudoindoxyl’ in Human Plasma

A study out of University of Florida published in the journal ACS Pharmacology & Translational Science found that the potency of powder kratom may be due not only to the increased level of 7-hydroxymitragynine (7-HMG), but the way the 7-HMG metabolizes in human plasma (Kamble 2020).

Fresh kratom consumed traditionally in Southeast Asia has been found to contain very low levels of 7-HMG. According to an editorial published by kratom researchers Abhisheak Sharma and Christopher McCurdy:

7-hydroxymitragynine is not produced by the plant but rather, oxidation of mitragynine occurs post-harvest during the drying, transportation, and/or manufacturing processes. Levels of 7-hydroxymitragynine in commercial kratom products in the United States are considerably (109–520%) higher than that of kratom preparations in native settings.

(Sharma 2020)

A 2019 study in mice showed that 7-HMG is also a metabolite of mitragynine, and levels of 7-HMG that were not metabolized from mitragynine stayed constant in the liver. The authors posited that “the analgesia induced by mitragynine appears to depend largely on formation of [7-HMG] as a metabolite and not on the parent compound.” (Kruegel 2019). This called into question whether a higher level of 7-HMG from the drying process contributes to potency at all. When asked about the Kruegel 2019 study on Kratom Science Podcast #45, Dr. Abhisheak Sharma replied:

That study has a drawback…Our body has two kind of metabolic enzymes. One is called Phase 1 metabolism and the other is called Phase 2 metabolism. So Phase 1 metabolism is a simple chemical reaction like oxidation, reduction, hydrolysis. And Phase 2 metabolism means the body, the liver will add a polar group to the molecule or its metabolite. That’s like glucunoride or certain amino acids. So the study was performed in liver microsomes, and liver microsomes cannot do that Phase 2 reaction. When we look at the structure of the 7-hydoxymitragynine, it has a free hydroxyl group. So it is very prone to glucunoride metabolism. So that study is like half…of metabolism, because you’re not looking at the full metabolism.

Kratom Science Podcast #45

The Kamble 2020 study, which Dr. Sharma also worked on, found that 7-HMG metabolizes even further in human plasma into “mitragynine pseudoindoxyl, an opioid that is even more potent than either mitragynine or 7-HMG”. As human metabolism differs from animal metabolism, this is not the case in monkey and rodent plasma, where levels of 7-HMG remain constant.

What consumers of US kratom products can take away from this research is that, while studies have shown kratom to run parallel to user reports about lesser adverse effects than that of classical opioids (lower physical dependence and little to no respiratory depression), 1) the dried kratom available in the US seems to be more potent than kratom prepared from fresh leaves, and therefore 2) kratom consumers should take care to moderate their consumption as long-term studies of consumers of kratom containing higher levels of 7-HMG have not been conducted as with consumers of traditional, fresh kratom.

Works cited:

Kamble, S. H., León, F., King, T. I., Berthold, E. C., Lopera-Londoño, C., Siva Rama Raju, K., Hampson, A. J., Sharma, A., Avery, B. A., McMahon, L. R., & McCurdy, C. R. (2020). Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy. ACS pharmacology & translational science, 3(6), 1063–1068. https://doi.org/10.1021/acsptsci.0c00075

Sharma, A., & McCurdy, C. R. (2020). Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder. Expert opinion on drug metabolism & toxicology, 1–3. Advance online publication. https://doi.org/10.1080/17425255.2021.1853706

Kruegel, A. C., Uprety, R., Grinnell, S. G., Langreck, C., Pekarskaya, E. A., Le Rouzic, V., Ansonoff, M., Gassaway, M. M., Pintar, J. E., Pasternak, G. W., Javitch, J. A., Majumdar, S., & Sames, D. (2019). 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS central science, 5(6), 992–1001. https://doi.org/10.1021/acscentsci.9b00141

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